Data mining using template-based molecular docking on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1RT inhibitors

Abstract

TIBO (Tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone) compounds are potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) that show a great promise for the treatment of AIDS. A structure-based molecular modeling approach based on template-based flexible docking simulation followed by 'Tabu clustering' was performed on a series of 46 TIBO derivatives considered as training set of HIV-1 NNRTIs. Four different templates of the highest active ligand (pIC(50) = 8.52) of the series were used. The results were reasonably satisfactory. A good correlation was observed between the biological activity and binding affinity of the compounds, which suggest that identified binding conformations of these inhibitors are reliable. Statistical modeling yielded satisfactory results (r(2) = 0.878). Our studies suggest that template-based docking followed by 'Tabu clustering' enhances the docking efficiency. Also, cross-validation with a test-set containing 16 compounds gave satisfactory results (r(2) = 0.836). Data mining of PubChem database yielded a total of 31 hits (25 novel TIBO like compounds, as well as, 6 novel scaffolds) with enhanced binding efficacy as hits. These hits may, be targeted toward potent lead-optimization and, help in designing and synthesizing novel compounds with enhanced therapeutic efficacy.

Predictions of Drug–Protein Interactions and Study of Magnetically Assisted Release Dynamics of 5-Fluorouracil from Soya Protein-Coated Iron Oxide Core–Shell Nanoparticles

“…Computer-aided drug design (CADD) approaches have been widely used to discover, develop, and analyze drugs and similar potential bioactive molecules, reducing time and cost. , These approaches are divided into ligand-based and structure-based drug designs. − The concept of structure-based drug design (SBDD) furnishes a deeper perceptive of the structure of the protein binding sites and various interlinkages coupled with them. − The principle of docking is based on an energy-based scoring relation that distinguishes the most fitted conformation of ligand when accommodated to the receptor binding pocket. − The extensive approach is based on the fact that lower energy scores suggest for more suitable binding of receptors and ligands in comparison to greater values of energy scores. In this way, the molecular docking aims at achieving a suitable ligand binding mode with the smallest energy .…”

Therapeutic strategies underpinning the development of novel techniques for the treatment of HIV infection

“…After steps of prefilters, a docking screening on the PubChem database finally yielded 20 compounds that might have enhanced binding affinities. In a later study, Sapre et al [55] improved the docking protocol by using incorporated templates, an enhanced pose clustering technique and a simplex evolution algorithm (MolDock SE) along with MolDock Grid. The more efficient docking protocol retrieved 25 novel TIBO-like compounds and six novel scaffolds from the PubChem database.…”

Ligand based 3D-QSAR modelling studies on 2-amino-6-aryl sulfonylbenzonitriles (AASBNs) as non-nucleoside reverse transcriptase inhibitors of HIV-1

“…25 Our earlier QSPR studies dealt with the lipophilicity of the AASBN series and the factors affecting it, 26 while the QSAR study was based on the utility of Kier-Hall electrotopological indices in depicting the substitution effects. 27 Computational methods have been instrumental in structure elucidation and drug development. These methods enhance the speed of the drug discovery process towards compounds with the desired activity profile.…”